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Effects of Intrabrachial Metacholine Infusion on Muscle Capillary Recruitment and Forearm Glucose Uptake during Physiological Hyperinsulinemia in Obese, Insulin-Resistant Individuals

The Lundberg Laboratory for Diabetes Research (G.M., M.S., L.S., S.G., P.L., P.-A.J.), Center of Excellence for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at Göteborg University, SE 405 30 Göteborg, Sweden; Department of Internal Medicine (G.M.), Section of Internal Medicine, Endocrine and Metabolic Sciences, Perugia University, I-06122, Perugia, Italy; and Department of Medicine (L.L.), Uppsala University Hospital, SE-431 80 Mölndal, Sweden

Address all correspondence and requests for reprints to: G. Murdolo, M.D., Ph.D., Department of Internal Medicine, Section of Internal Medicine, Endocrine and Metabolic Sciences, Perugia University, Via Enrico Dal Pozzo, I-06122, Perugia, Italy. E-mail: tugiuseppe.murdolo{at}medic.gu.seut and tugmurdolo{at}tiscalinet.itut.

Context: Impairment of insulin-mediated capillary recruitment in skeletal muscle contributes to a hampered glucose uptake in obesity.

Objective: The objective of this study was to evaluate whether metacholine (MCh), a nitric oxide vasodilator, potentiates muscle capillary recruitment and forearm glucose uptake (FGU) during physiological hyperinsulinemia.

Design: The double-forearm technique [i.e. infused vs. control (Ctrl) forearm] was combined with im microdialysis during an oral glucose tolerance test in 15 nondiabetic, obese subjects divided into a group of insulin-resistant (IR) (n = 7) and insulin-sensitive (n = 8) individuals.

Results: After the oral glucose tolerance test, forearm blood flow in the Ctrl forearm was unchanged, whereas it increased about 3-fold (P < 0.0001 vs. baseline) in response to MCh. Capillary permeability surface area product for glucose (PS_glu) (capillary recruitment), FGU, and interstitial insulin concentrations increased significantly over time (P < 0.001) in both forearms. Compared with insulin-sensitive, the IR subjects exhibited lower PS_glu (P < 0.001) and FGU (P < 0.01) in the Ctrl arm, whereas this difference was insignificant in the MCh arm despite the blunted forearm blood flow increase. Moreover, in IR individuals MCh significantly (P < 0.05) ameliorated the delayed onset of insulin action, i.e. the FGU response to hyperinsulinemia. Finally, we found PS_glu to be a strong and independent predictor of FGU response (adjusted R² 0.72; P < 0.0001).

Conclusions: MCh-induced vasodilation may improve the microvascular and metabolic responses to physiological hyperinsulinemia in obese, IR individuals. Further studies are required to unravel whether stimulation of nitric oxide production in skeletal muscle may represent an attractive therapeutic approach to bypassing cellular resistance to glucose disposal.